A Formal Total Synthesis of Securinine via an Intramolecular [4+2] Cycloaddition Reaction

An intramolecular Diels-Alder reaction of the enol ester derived from 2-acetylpyridine and sorbic anhydride gave the cycloaddition product, stereoselectively, which was further converted into the key intermediate for the synthesis of securinine.Securinine, 1 a member of the Securinega family of alkaloids having a tetracyclic indolizidine skeleton with an α,β-unsaturated γ-lactone, was originally isolated from Securinega suffruticasa, 2 and its structure was determined by chemical and spectroscopic studies, 3,4 and also by X-Ray crystallographic analysis 5 as shown in Figure 1.N O O H Figure 1.The structure of securinine.Since this alkaloid has been shown to exhibit a stereospecific GABAA receptor antagonist activity, a number of syntheses and synthetic approaches were developed with the hope of understanding the shape of the GABAA receptor site. 6To date, only two total syntheses of securinine have been reported. 7The first total synthesis of securinine was published by Horii and co-workers in 1967, 7a where cyclohexane-1,2-dione was employed as the A-ring precursor and 2-lithiopyridine was introduced as the C-ring moiety.Although a number of synthetic approaches to this alkaloid were developed after Horii's synthesis, most of them could not reach to its total synthesis.Very recently, a concise total synthesis of securinine was achieved by using a ring closing metathesis leading to the construction of the A-ring, as a key reaction by Liras and co-workers.7b Due to the attractive biological activity and also its unique structural feature, we are also interested in developing a novel strategy for the synthesis of securinine, in D Thus, we investigated the preparation of the enol ester (8), a precursor for Diels-Alder reaction, as follows.The ketal (2), derived from 2-acetylpyridine (1) and ethylene glycol, was alkylated with benzyl bromide in acetonitrile to afford the quaternary salt, which on successive reduction with sodium borohydride, then over platinum oxide under an atmospheric pressure of hydrogen gave the piperidine derivative (5).After removal of the ketal group of 5 by acid treatment, the resulting acetyl compound (6) was treated with sorbic anhydride in the presence of lithium hexamethyldisilazide in THF to give the conjugated enol ester (7).Deconjugation reaction of 7 was achieved by treatment with lithium hexamethyldisilazide, followed by protonation with acetic acid 10 to provide the enol ester (8) (Scheme 1).